Synthesis of (±)-Bakkenolide-A and Its C-7, C-10, and C-7,10 Epimers by Means of an Intramolecular Diels−Alder Reaction

Abstract

(+/-)-bakkenolide-A (1) was prepared in five steps from ethyl 4-benzyloxyacetoacetate by sequential alkylations with tiglyl bromide and (Z)-5-bromo-1,3-pentadiene, followed by an intramolecular Diels-Alder reaction of (E,Z)-triene 25b as the key step. The hydrindane cycloadduct 28 was subjected to hydrogenation and spontaneous or acid-catalyzed lactonization, followed by a Witttig reaction to introduce the exocyclic methylene group of 1. The known 7-epibakkenolide-A (2) and novel 10-epi- and 7,10-diepibakkenolide-A (3 and 4, respectively) stereoisomers were obtained as minor byproducts. When (E)-5-bromo-1,3-pentadiene was used instead of the Z-isomer, the 10-epi- and 7,10-diepibakkenolides were the major products. In both cases exo cyclization was preferred over endo. An alternative approach was based on a similar intramolecular Diels-Alder cycloaddition, using dimethyl malonate instead of ethyl 4-benzyloxyacetoacetate as the starting material for the double alkylation preceding the cycloaddition step. The cycloadduct was then converted into the corresponding alpha-phenylseleno propargyl esters 16 or 22. However, attempted formation of the spiro center by a radical cyclization resulted chiefly in reductive deselenization.

Methodology for the Construction of the Bicyclo[4.3.0]nonane Core

“…An approach to the bakkane skeleton through successive alkylations of dimethylmalonate led to Diels-Alder precursor 112, which provided a cishydrindane 113 for further elaboration [55,56]. More recent work has expounded upon this route to utilize 118 and α,β-unsaturated aldehydes to provide adducts similar in nature to 114, and has been A benefit to the Diels-Alder is that it requires so little to effect cyclization, and can be used in combination with other reactions (see Scheme 18).…”

“…More recent work has expounded upon this route to utilize 118 and α,β-unsaturated aldehydes to provide adducts similar in nature to 114, and has been A benefit to the Diels-Alder is that it requires so little to effect cyclization, and can be used in combination with other reactions (see Scheme 18). An approach to the bakkane skeleton through successive alkylations of dimethylmalonate led to Diels-Alder precursor 112, which provided a cis-hydrindane 113 for further elaboration [55,56]. More recent work has expounded upon this route to utilize 118 and α,β-unsaturated aldehydes to provide adducts similar in nature to 114, and has been applied to the synthesis of nootakone [57].…”

A síntese dos sesquiterpenos baquenolidas

“…Reddy 34 utiliza uma estratégia interessante envolvendo uma reação de Diels-Alder intermolecular em tandem com uma reação de aldol para gerar o sistema hidrindano. O grupo de Greene 35 continua explorando variações sobre a cicloadição [2+2], enquanto o grupo de Back 36 também se interessou pela aplicação da reação de Diels-Alder intramolecular para gerar o sistema completo da B-A. Neste último trabalho a ciclização da reação IMDA é conduzida em condições extremamente vigorosas e leva a uma mistura diaestereomérica muito complexa.…”

Natural sesquiterpenoids

“…339 Racemic bakkenolide A has been synthesised in five steps. 340 19 Guaiane, pseudoguaiane, xanthane, rotundane, patchoulane, carabrane, trixane and bourbonane O-Methylguaianediol 360 has been obtained from the Red Sea sponge Diacarnus erythraenus. 341 Two other compounds of this type, 361 and 362, have been isolated from the soft coral Sarcophyton buitendijki, collected in the Indian Ocean.…”